Taylor, Donald
(2014)
Breast cancer metastatic dormancy and emergence in the hepatic niche.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Breast cancer metastatic dormancy allows tumors to avoid clinical detection and evade treatment leading to recurrence after years or even decades, with devastating mortality rates. How the aggressive carcinoma cells that initially underwent a cancer-associated Epithelial to Mesenchymal Transition (EMT) from the primary tumor to disseminate and maintain a long-term, clinically undetectable state in an ectopic site is unknown. Clinical evidence suggests that many of the extravasated breast cancer cells partially revert their mesenchymal phenotype to an epithelial phenotype (MErT). This transition coincides with resistance to chemotherapy and may be a precursor to metastatic dormancy.
We first investigated the boundary probabilities under which proliferating micrometastases would engage dormancy. We developed a two-state Markov chain Monte Carlo simulation that modeled balanced proliferation. This modeling determined that balanced proliferation invoked dormancy only between a 49.7-50.8% survival probability range. This narrow window strongly suggests that cellular quiescence most likely explains dormancy. The implications for treatment and chemoresistance of metastases are discussed.
We also investigated early events that allow for metastatic dormancy. We postulated that the metastatic niche must be prepared by stresses that destabilize the parenchyma. Primary rat and human hepatocytes were challenged with epidermal growth factor (EGF) prior to MDA-MB-231 or MCF-7 inoculation in 2D and 3D bioreactor cultures. MDA-MB-231 cells with exogenously modulated E-cadherin were intrasplenically injected into NOD/scid gamma mice in order to investigate E-cadherin’s role in establishing liver metastases. To explore emergence from metastatic dormancy we investigated whether hepatic non-parenchymal cells (NPCs) contributed to metastatic breast cancer cell outgrowth and a mesenchymal phenotypic shift indicative of emergence. We found that the pre-stressed liver microenvironment confers a metastatic seeding advantage to the breast cancer cells at least in part by promoting a more pronounced epithelial reversion marked by E-cadherin up-regulation. In vivo studies confirmed that E-cadherin inversely correlates to metastatic proliferation. We also concluded that NPCs impart a partial mesenchymal shift to the MCF-7 cells thus conferring a grow-out advantage.
Taken together these investigations suggest that the metastatic microenvironment plays a role in metastatic competency through EMT/MErT plasticity and should be considered a potential target for ablating disseminated tumor cells.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
29 January 2014 |
| Date Type: |
Publication |
| Defense Date: |
8 November 2013 |
| Approval Date: |
29 January 2014 |
| Submission Date: |
27 November 2013 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
163 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Breast cancer, metastasis, metastatic dormancy |
| Date Deposited: |
29 Jan 2014 18:01 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20120 |
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